SUMMARY

• The CREDENCE study conducted safety assessments using on-treatment analyses (data from patients with a safety outcome while receiving INVOKANA or placebo [PBO] or within 30 days after discontinuation of INVOKANA or PBO).¹
• The CANVAS Program^2,3 (N=10,142), comprised of 2 large INVOKANA cardiovascular (CV) outcome studies, CANVAS^4,5 and CANVAS-R^6,7, conducted safety assessments using an on-treatment analysis (data from patients with a safety outcome while receiving INVOKANA or PBO or within 30 days after discontinuation of INVOKANA or PBO). CANVAS-R also evaluated change in estimated glomerular filtration rate (eGFR) from baseline to the last off-treatment value ~30 days after study drug discontinuation.⁸

CLINICAL DATA

CREDENCE

CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) was a randomized, double-blind, PBO-controlled, parallel-group, multicenter, event-driven clinical trial (N=4401) designed to assess the effects of INVOKANA (100 mg) compared to PBO on clinically important renal outcomes in people with type 2 diabetes mellitus (T2DM) and established chronic kidney disease (eGFR 30 to <90 mL/min/1.73 m²) and albuminuria (ratio of albumin to creatinine >300 to 5000 mg/g), who were receiving a stable, maximum-tolerated or labelled dose (for ≥4 weeks prior to randomization) of an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker.^1,9,10

• At the conclusion of the CREDENCE trial (median follow-up of 2.62 years), 24.7% (n=543) and 29.9% (n=658) of patients treated with INVOKANA and PBO, respectively, discontinued the assigned regimen prematurely.¹⁰
• Extensive efforts were made to obtain full outcome data for all participants, including those who discontinued study medication, during the final follow-up, with all but 6 patients (99.9%) with known vital status at the end of the trial.^1,10
• Safety assessments were conducted using on-treatment analysis (data from patients with a safety outcome while receiving INVOKANA or PBO or within 30 days after discontinuation of drug or PBO), except for the numbers of amputation, fracture, and cancer events, which were determined in the on-study population. Please refer to the Perkovic 2019 published paper for full safety outcomes.¹

The CANVAS Program

• The CANVAS Program^2,3 (N=10,142) comprises the 2 large INVOKANA CV outcome studies, CANVAS^4,5 and CANVAS-R^6,7, and includes a prespecified integrated analysis of these studies to meet the Food and Drug Administration postmarketing requirement for CV safety. This analysis also evaluates potential for CV protection of INVOKANA in patients with T2DM who had prior history of CV disease or ≥2 CV risk factors.^2,3 The integrated analysis also evaluated the effects of INVOKANA on renal and safety outcomes.³
• In the CANVAS Program, 29.2% and 29.9% of patients treated with INVOKANA and PBO, respectively, discontinued the assigned regimen prematurely.³
• Those patients who prematurely discontinued continued scheduled follow-up whenever possible. Extensive efforts were made to obtain full outcome data for all participants during the final follow-up. Patients were followed for a mean of 188.2 weeks.³
• Safety assessments were conducted using on-treatment analysis (data from patients with a safety outcome while receiving INVOKANA or PBO or within 30 days after discontinuation of drug or PBO), except for fracture, amputation, cancer, and diabetic ketoacidosis (DKA) outcomes, which included all events at any time point in all patients who underwent randomization and received at least 1 dose of INVOKANA or PBO. Please refer to the Neal 2017 published paper for full safety outcomes.³
• One secondary objective in CANVAS-R included change in eGFR from baseline to the last off-treatment value ~30 days after study drug discontinuation.⁸ Among patients who were re-evaluated ~30 days after treatment discontinuation, change from baseline to off-treatment eGFR was higher, on average, with INVOKANA vs PBO (difference of 2.6 mL/min/1.73 m² [95% CI: 1.8-3.4]).¹¹ See Figure: eGFR Over Time and After a Median of 30 Days Off-Treatment in CANVAS-R Study.

Renal Function Assessments After Drug Discontinuation

• Follow-up blood chemistry studies were not routinely conducted in the INVOKANA phase 3 glycemic control studies. However, among a subset of patients (n=396) who had renal function measurements after discontinuation of study drug, eGFR increased toward baseline after discontinuation of INVOKANA, concluding that there was no meaningful difference for % change from baseline in eGFR at follow-up with INVOKANA.¹²
• Please also refer to CANVAS-R results as described in the CANVAS Program section.

Drug Discontinuation Prior to Surgical Procedures

• Withhold INVOKANA at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKANA once the patient is clinically stable and has resumed oral intake.¹³

Drug Discontinuation in Clinical Situations

• Withhold INVOKANA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKANA once the patient is clinically stable and has resumed oral intake. Discontinue INVOKANA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting.¹³
• Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs; discontinue INVOKANA if these complications occur.¹³
• If suspected with necrotizing fasciitis of the perineum (Fournier’s gangrene), discontinue INVOKANA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.¹³
• If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve.¹³

Recommendations and Management

The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) held a Consensus Conference, “AACE/ACE Scientific and Clinical Review: Association of SGLT2 Inhibitors and Diabetic Ketoacidosis,” in which experts convened in October 2015 to conduct an intensive review of available scientific and clinical data on the possible relationship of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and DKA. To minimize risk of DKA associated with SGLT2i, AACE recommends the following¹⁴:

• Consider stopping the SGLT2i at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity, such as running a marathon.
• Stop the drug immediately for emergency surgery or any extreme stress event.

AACE/ACE noted that diagnosis of DKA is often missed or delayed due to atypical patient presentation involving lower-than-anticipated glucose or other misleading laboratory values. Therefore, AACE/ACE encourages greater healthcare professional education that focuses on proper diagnosis and treatment of DKA with SGLT2i.¹⁴

The American Diabetes Association (ADA) published a report regarding international consensus on risk management of DKA in patients with T1DM treated with SGLTi. The Consensus Report reviews current data regarding SGLTi use and provides recommendations to minimize the risk of SGLTi in type 1 diabetic patients.¹⁵

• To minimize the risk of DKA associated with SGLTi, the ADA recommends the following:
  • SGLTi therapy should be discontinued following any nausea, vomiting, or abdominal discomfort, with subsequent evaluation of ketosis.
  • SGLTi therapy should be withheld if the patient is hospitalized, acutely ill, or unable to eat/drink, as well as prior to any medical procedure (especially if unable to eat/drink; ideally for 3 days). Therapy should also be withheld during switching of insulin therapy and when changing from manual mode to auto mode on an automated insulin delivery system until insulin doses are adjusted, blood glucose is controlled, and ketone levels are normal.
  • If ketones are elevated, SGLTi therapy should be discontinued. Treatment, including insulin, carbohydrates, and hydration, should be initiated immediately to avoid DKA and potential hospitalization. If symptoms and/or ketones worsen, patients should seek immediate medical assistance.
  • The ADA Consensus Report encourages patient and clinician education regarding DKA risk factors and symptoms, euglycemic DKA, ketone monitoring, and treatment protocols.

Withdrawal/Rebound Effect After Drug Discontinuation

• No information is available regarding INVOKANA and withdrawal or rebound effects after drug discontinuation.

Nonmedical Switching

• Effects of nonmedical switching of T2DM medications in the US from a cohort of commercially insured patients were also measured in a study by Blonde et al (2018).¹⁶

Published postmarketing Case reports

• A case report of recurrent euglycemic DKA after INVOKANA discontinuation was published.¹⁷
• A few cases were published of patients with euglycemic DKA who had prolonged glucosuria after discontinuation of an SGLT2i (including INVOKANA).¹⁸

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 21 January 2025.